| First Author | Spolitu S | Year | 2019 |
| Journal | Circ Res | Volume | 124 |
| Issue | 1 | Pages | 38-51 |
| PubMed ID | 30582457 | Mgi Jnum | J:295085 |
| Mgi Id | MGI:6459627 | Doi | 10.1161/CIRCRESAHA.118.313648 |
| Citation | Spolitu S, et al. (2019) Hepatic Glucagon Signaling Regulates PCSK9 and Low-Density Lipoprotein Cholesterol. Circ Res 124(1):38-51 |
| abstractText | RATIONALE: Glucagon is a key hormone that regulates the adaptive metabolic responses to fasting. In addition to maintaining glucose homeostasis, glucagon participates in the regulation of cholesterol metabolism; however, the molecular pathways underlying this effect are incompletely understood. OBJECTIVE: We sought to determine the role of hepatic Gcgr (glucagon receptor) signaling in plasma cholesterol regulation and identify its underlying molecular mechanisms. METHODS AND RESULTS: We show that Gcgr signaling plays an essential role in LDL-C (low-density lipoprotein cholesterol) homeostasis through regulating the PCSK9 (proprotein convertase subtilisin/kexin type 9) levels. Silencing of hepatic Gcgr or inhibition of glucagon action increased hepatic and plasma PCSK9 and resulted in lower LDLR (LDL receptor) protein and increased plasma LDL-C. Conversely, treatment of wild-type (WT) mice with glucagon lowered LDL-C levels, whereas this response was abrogated in Pcsk9(-/-) and Ldlr(-/-) mice. Our gain- and loss-of-function studies identified Epac2 (exchange protein activated by cAMP-2) and Rap1 (Ras-related protein-1) as the downstream mediators of glucagon's action on PCSK9 homeostasis. Moreover, mechanistic studies revealed that glucagon affected the half-life of PCSK9 protein without changing the level of its mRNA, indicating that Gcgr signaling regulates PCSK9 degradation. CONCLUSIONS: These findings provide novel insights into the molecular interplay between hepatic glucagon signaling and lipid metabolism and describe a new posttranscriptional mechanism of PCSK9 regulation. |
